Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma.
Aruna MarchettoShunya OhmuraMartin F OrthMaximilian Martin Ludwig KnottMaria Vittoria ColomboChiara ArrigoniVictor BardinetDavid SaucierFabienne S WehweckJing LiStefanie SteinJulia S GerkeMichaela C BaldaufJulian MusaMarlene DallmayerLaura Romero-PérezTilman L B HöltingJames F AmatrudaAndrea CossarizzaAnton G HenssenThomas KirchnerMatteo MorettiFlorencia Cidre-AranazGiuseppina SanninoThomas G P GrünewaldPublished in: Nature communications (2020)
Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.
Keyphrases
- transcription factor
- oxidative stress
- mesenchymal stem cells
- genome wide identification
- childhood cancer
- dna binding
- umbilical cord
- climate change
- dna damage
- single cell
- ischemia reperfusion injury
- induced apoptosis
- diabetic rats
- genome wide
- poor prognosis
- bone marrow
- young adults
- randomized controlled trial
- gene expression
- stem cells
- rna seq
- electronic health record
- dna methylation
- systematic review
- heat shock
- drug induced
- binding protein
- adverse drug
- emergency department
- machine learning
- endoplasmic reticulum stress
- heat stress
- bioinformatics analysis